J Biol Chem. 2002 Oct 25;277(43):40594-601. Epub 2002 Aug 20. JAK-STAT signaling mediates gangliosides-induced inflammatory responses in brain microglial cells.
Kim OS, Park EJ, Joe EH, Jou I.
Department of Pharmacology, School of Medicine, Ajou University, Suwon 442-721, Korea.
Neuronal cell membranes are particularly rich in gangliosides, which play important roles in brain physiology and pathology. Previously, we reported that gangliosides could act as microglial activators and are thus likely to participate in many neuronal diseases. In the present study we provide evidence that JAK-STAT inflammatory signaling mediates gangliosides-stimulated microglial activation. Both in rat primary microglia and murine BV2 microglial cells, gangliosides stimulated nuclear factor binding to GAS/ISRE elements, which are known to be STAT-binding sites. Consistent with this, gangliosides rapidly activated JAK1 and JAK2 and induced phosphorylation of STAT1 and STAT3. In addition, gangliosides increased transcription of the inflammation-associated genes inducible nitric-oxide synthase, ICAM-1, and MCP-1, which are reported to contain STAT-binding elements in their promoter regions. AG490, a JAK inhibitor, reduced induction of these genes, nuclear factor binding activity, and activation of STAT1 and -3 in gangliosides-treated microglia. AG490 also inhibited gangliosides-induced release of nitric oxide, an inflammation hallmark. Furthermore, AG490 markedly reduced activation of ERK1/2 MAPK, indicating that ERKs act downstream of JAK-STAT signaling during microglial activation. However, AG490 did not affect activation of p38 MAPK. We also report that the sialic acid residues present on gangliosides may be one of the essential components in activation of JAK-STAT signaling. The present study indicates that JAK-STAT signaling is an early event in gangliosides-induced brain inflammatory responses.
PMID:_12191995
J Biol Chem. 2003 Jan 24;278(4):2118-23. Epub 2002 Nov 12. Src kinase mediates phosphatidylinositol 3-kinase/Akt-dependent rapid endothelial nitric-oxide synthase activation by estrogen.
Haynes MP, Li L, Sinha D, Russell KS, Hisamoto K, Baron R, Collinge M, Sessa WC, Bender JR.
Section of Cardiovascular Medicine, Department of Pharmacology, Boyer Center for Molecular Medicine, Yale University School of Medicine, New Haven, Connecticut 06536, USA.
17beta-Estradiol activates endothelial nitric oxide synthase (eNOS), enhancing nitric oxide (NO) release from endothelial cells via the phosphatidylinositol 3-kinase (PI3-kinase)/Akt pathway. The upstream regulators of this pathway are unknown. We now demonstrate that 17beta-estradiol rapidly activates eNOS through Src kinase in human endothelial cells. The Src family kinase specific-inhibitor 4-amino-5-(4-chlorophenyl)-7-(t-butyl)pyrazolo[3,4-d]pyrimidine (PP2) abrogates 17beta-estradiol- but not ionomycin-stimulated NO release. Consistent with these results, PP2 blocked 17beta-estradiol-induced Akt phosphorylation but did not inhibit NO release from cells transduced with a constitutively active Akt. PP2 abrogated 17beta-estradiol-induced activation of PI3-kinase, indicating that the PP2-inhibitable kinase is upstream of PI3-kinase and Akt. A 17beta-estradiol-induced estrogen receptor/c-Src association correlated with rapid c-Src phosphorylation. Moreover, transfection of kinase-dead c-Src inhibited 17beta-estradiol-induced Akt phosphorylation, whereas constitutively active c-Src increased basal Akt phosphorylation. Estrogen stimulation of murine embryonic fibroblasts with homozygous deletions of the c-src, fyn, and yes genes failed to induce Akt phosphorylation, whereas cells maintaining c-Src expression demonstrated estrogen-induced Akt activation. Estrogen rapidly activated c-Src inducing an estrogen receptor, c-Src, and P85 (regulatory subunit of PI3-kinase) complex formation. This complex formation results in the successive activation of PI3-kinase, Akt, and eNOS with consequent enhanced NO release, implicating c-Src as a critical upstream regulator of the estrogen-stimulated PI3-kinase/Akt/eNOS pathway.
PMID:_12431978
G Ital Nefrol. 2002 May-Jun;19(3):278-85. [Progression of chronic renal failure in remnant rats: role of arginase inhibition]
[Article in Italian]
Pisani A, Uccello F, Cesaro A, Alfieri R, Comi N, Mirenghi F, Serio V, Sabbatini M.
Cattedra di Nefrologia Medica, Universita degli Studi Federico II, Napoli.
BACKGROUND: Oral administration of arginine to remnant (REM) rats (5/6 nx) slows the progression of chronic renal failure through a nitric-oxide(NO)-dependent mechanism. We have recently shown that inhibition of arginase, the main metabolic pathway of arginine, was able to induce similar results on renal dynamics (GIN: 2001, 18:285-290). Aim of the present study was to test whether these changes were mediated by increased availability of arginine-derived NO. Methods. Three Groups of REM rats were studied for 8 weeks after surgery: 1) untreated REM (Group REM); 2) REM rats treated with arginine (1%) in tap water (Group ARG); 3) REM rats administered a Mn++-free diet, to induce partial inhibition of arginase (Group MNF). Normal unmanipulated rats were used as controls (Group NOR). RESULTS: Liver arginase activity was significantly depressed only in MNF-rats (-35% vs. REM, p < 0.01). Blood pressure was significantly lower in Group MNF vs. ARG and REM after 6 weeks (p < 0.05). Proteinuria was significantly decreased in Group ARG (-42%, p < 0.05 vs. REM) and even more in Group MNF (-57%, p < 0.01). ARG plasma levels, decreased in REM rats (-41% vs. Group CON), were normalized in Group ARG (p < 0.01 vs. Group REM); arginase inhibition was able to increase such levels in Group MNF (+38% vs. REM) and this resulted in a proportional rise in urinary nitrite excretion (+33% vs. REM), grossly depressed in REM rats. Renal arginase activity was lower in all the Groups of remnant rats vs. Group NOR, but intrarenal concentrations of ARG were significantly lower only in rats of Group MNF (p < 0.05 vs. all the other Groups). Histological examination showed that MNF-rats had a glomerular sclerosis index lower than in the other Groups (p < 0.05 vs. Group REM and ARG). CONCLUSIONS: In conclusion, inhibition of arginase in remnant rats slows the progression of CRF and preserves renal histology through a direct and/or indirect NO-dependent mechanism.
PMID:_12195395
J Biol Chem. 2002 Nov 8;277(45):42447-55. Epub 2002 Aug 28. The modulation of mitochondrial nitric-oxide synthase activity in rat brain development.
Riobo NA, Melani M, Sanjuan N, Fiszman ML, Gravielle MC, Carreras MC, Cadenas E, Poderoso JJ.
Laboratory of Oxygen Metabolism, University Hospital, Av. Cordoba 2351, 1120 Buenos Aires, Argentina.
Different mitochondrial nitric-oxide synthase (mtNOS) isoforms have been described in rat and mouse tissues, such as liver, thymus, skeletal muscle, and more recently, heart and brain. The modulation of these variants by thyroid status, hypoxia, or gene deficiency opens a broad spectrum of mtNOS-dependent tissue-specific functions. In this study, a new NOS variant is described in rat brain with an M(r) of 144 kDa and mainly localized in the inner mitochondrial membrane. During rat brain maturation, the expression and activity of mtNOS were maximal at the late embryonic stages and early postnatal days followed by a decreased expression in the adult stage (100 +/- 9 versus 19 +/- 2 pmol of [(3)H]citrulline/min/mg of protein, respectively). This temporal pattern was opposite to that of the cytosolic 157-kDa nNOS protein. Mitochondrial redox changes followed the variations in mtNOS activity: mtNOS-dependent production of hydrogen peroxide was maximal in newborns and decreased markedly in the adult stage, thus reflecting the production and utilization of mitochondrial matrix nitric oxide. Moreover, the activity of brain Mn-superoxide dismutase followed a developmental pattern similar to that of mtNOS. Cerebellar granular cells isolated from newborn rats and with high mtNOS activity exhibited maximal proliferation rates, which were decreased by modifying the levels of either hydrogen peroxide or nitric oxide. Altogether, these findings support the notion that a coordinated modulation of mtNOS and Mn-superoxide dismutase contributes to establish the rat brain redox status and participate in the normal physiology of brain development.
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